Public Release: 16-Jun-2011
Tips from the journals of the American Society for Microbiology

Some new research on a bacterial predator that feeds on other bacteria may lead to new ammunition against biofilms. The research is published in the June 2011 issue of the Journal of Bacteriology.

Bacterial pathogens frequently form biofilms, which adhere to surfaces, and which are far more resistant to antibiotics than are individual bacteria. Biofilms are the culprits in a wide variety of infections, which range from minor problems to major chronic problems, to the lethal.

The predatory bacteria, members of the genus Bdellovibrio, eat their prey, larger, oft-pathogenic bacteria, from the inside. They have other amazing attributes, including their incredible speed, 100 body lengths per second, propelled by a single sheathed flagellum, which leads their student, Liz Sockett of the University of Nottingham, UK, to characterize them as the Bugatti Veyron (top speed 250 mpg) of the microbial world. But in the new research, Sockett's colleagues Carey Lambert and Andy Fenton show that Bdellovibrio bacteriovorus can switch "engines"--who knew it had two?--and crawl along at a snail-like 20 body lengths per hour. That laid back locomotion "lets the Bdellovibrio exit from a bacterial prey cell which it has finished digesting, and crawl across a solid surface to find other bacterial prey to invade," says Sockett.

It is important to understand and preserve this laid back form of locomotion "if Bdellovibrio are to be used in the future to kill pathogenic bacteria on solid surfaces, like medical biofilms, where there may be too little liquid for swimming," says Sockett. Others, she says, have identified the similarly slow engines in the Bdellovibrio relatives, the Myxobacteria, and comparing the two engines may illuminate the mechanics in ways that could lead to medical applications, she says.

As for those medical applications, suffice it to say that biofilms play a role in urinary tract infections, and middle ear infections; they form on catheters, on teeth and in gums (dental plaque, and gingivitis, respectively), and they are common in lethal infections such as cystic fibrosis and endocarditis. "The hope is that one day Bdellovibrio in slow gear will mop them up."

New research suggests that cholesterol boosts resistance in Helicobacter pylori both to many antibiotics and to the endogenous antimicrobial peptide, LL-37. A complete understanding of the pathway of cholesterol uptake might lead to novel strategies thwarting H. pylori by blocking that pathway, says corresponding author David McGee of Louisiana State University. The research is published in the June 2011 issue of the journal Antimicrobial Agents and Chemotherapy.

H. pylori infects one third of Americans, causing gastritis and peptic ulcers, and costing $10 billion annually. Antibiotic therapy is recommended, but resistance, often leading to treatment failures, is becoming increasingly common, even following the now-standard triple drug therapy.

In the study, the investigators grew H. pylori in the presence or absence of cholesterol, and treated the bacteria with different classes and concentrations of antibiotics, comparing the populations of surviving bacteria. "We found that H. pylori grown with cholesterol displayed a very dramatic increase in resistance to many antibiotics, bismuth, and to LL-37," says McGee.

"It would be important to learn whether we can manipulate the ability to clear H. pylori infections in animals and humans by lowering cholesterol either through dietary means or cholesterol-lowering drugs (statins)," says McGee. "There are already data showing that H. pylori-infected patients have elevated serum cholesterol levels, suggesting the bacteria manipulate the human host to produce more cholesterol." Additionally, he says, a study of 500 patients found that taking statins lowered the severity of chronic gastritis, which is also caused by H. pylori. But some statins work, and others don't, he says. And so far, no studies have combined antibiotics with statins. Thus, it is too soon to make recommendations to patients on their use to lower cholesterol, he says.

Interestingly, McGee says his research would not have been possible without the help of a high school student. Alika George, now an undergraduate at the University of Louisiana, collected some of the data, and urged McGee to include pepto bismol (bismuth) in the study, while taking part in a summer enrichment program for minority high school students, which was supported by Louisiana State University's Office of Multicultural Affairs. "I feel it is vital to be supportive of programs like this to give students opportunities they otherwise would not have had," says McGee.

Soil-dwelling bacteria of the genus Frankia have the potential to produce a multitude of natural products, including antibiotics, herbicides, pigments, anticancer agents, and other useful products, according to Bradley S. Moore of the Scripps Oceanographic Institute, La Jolla, and his collaborators in an article in the June 2011 issue of the journal Applied and Environmental Microbiology.

The researchers found genetic structures in this bacterium that resemble those of various valuable natural product categories through bioinformatics and genome mining. "This tremendous biosynthetic capacity is reminiscent of many industrially important bacteria such as those belonging to the genus, Streptomyces that produce the majority of the natural antibiotics used as drugs," says Moore.

"To see this capacity in a well-known microbe not previously exploited for its chemical richness was very rewarding from both an applied and basic science point of view," says Moore. Frankia are nitrogen-fixing bacteria that live in symbiosis with actinorhizal plants (whose ranks include beech and cherry trees, and various gourd-producing plants). "Since the vast majority of the deduced [biosynthetic] pathways are unique to Frankia, it suggests that they employ a very complex and specialized communication with their plant host to establish and maintain their symbiosis. So lots to discover there."

Frankia have not previously been exploited partly because these bacteria are difficult to grow in the lab. But new genetic methods make it easier to transplant genes for promising natural products from Frankia into "more user-friendly host bacteria for production," says Moore.

Moreover, genome mining, a recent technique that involves searching for genetic sequences, was critical to the results, and "complementary to the far more laborious traditional natural product drug discovery that has gone unchanged for decades," says Moore. A greater understanding of how complex organic molecules are synthesized in nature laid additional groundwork for this, and for "a new revolution in the discovery of natural chemicals that will fuel new research into what functions these chemicals play in nature, and how they can be used to benefit society," says Moore.

The project grew out of a graduate class that Moore and Daniel Udwary (then his post-doc, now at the University of Rhode Island) taught on "Microbial Genome Mining," says Moore. Each student in the class researched a group of biosynthetic gene clusters that Moore and Udwary preselected. The students--who are the majority of coauthors on the paper--annotated their genes and based on biosynthetic principles, and predicted pathways leading to putative natural products. They then worked with the laboratories of Pieter Dorrestein at the University of California, San Diego (a mass spec specialist) and Lou Tisa at the University of New Hampshire (a Frankia biologist) to conduct preliminary proteomic and metabolomic analyses to probe whether the predicted pathways were operative, and whether small molecule chemistry was evident.

Laboratory-grown gingival cells treated with vitamin D boosted their production of an endogenous antibiotic, and killed more bacteria than untreated cells, according to a paper in the June 2011 issue of the journal Infection and Immunity. The research suggests that vitamin D can help protect the gums from bacterial infections that lead to gingivitis and periodontitis. Periodontitis affects up to 50 percent of the US population, is a major cause of tooth loss, and can also contribute to heart disease. Most Americans are deficient in vitamin D.

His interest piqued by another laboratory's discovery that vitamin D could stimulate white blood cells to produce natural proteins that have antibiotic activity, Gill Diamond of the UMDNJ--New Jersey Dental School, Newark, showed that vitamin D could stimulate lung cells to produce LL-37, a natural antibiotic protein, and kill more bacteria. That suggested that , vitamin D might help cystic fibrosis patients. Next, in the new research, he showed that vitamin D has the same effct on gingival cells.

Then, Diamond found that vitamin D also stimulates gingival cells to produce another protein, called TREM-1, which had not been well-studied, but which was thought to be made by white blood cells. He found that it boosts production of pro-inflammatory cytokines.

The new research also showed that vitamin D coordinates expression of a number of genes not previously considered to be part of the vitamin D pathway. Those genes may be involved in additional infection-fighting pathways. A more comprehensive understanding of how vitamin D carries out this regulation at the molecular level--something Diamond hopes to investigate--will enable targeted therapies using vitamin D, he says.

Interestingly, Diamond also found that lung and gum cells appear to have the ability to activate inactive forms of vitamin D, says Diamond. "This means that we may even be able to use vitamin D therapy topically, if that proves true."

Vitamin D has become a hot area of research in recent years. In addition to infectious diseases, studies suggest that it has protective effects against autoimmune diseases, and certain cancers.

Diamond says that after he began conducting research on vitamin D, he began taking it as a supplement. Since then, "I have had only one cold in four years, and that one lasted only three days," he says. "Other people I've met who have done the same have seen similar results. We are trying to figure out how it's working, and what other infectious diseases can be mitigated by it."

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